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6 Ageing and growth hormone status
6 Ageing and growth hormone status A N D R E W A. T O O G O O D * MB, ChB, MRCP Specialist Registrar in Endocrinology and Diabetes
S T E P H E N M. S H A L E T MD, FRCP Professor of Endocrinology Department (~{Endocrinology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester; M20 4BX, UK
Organic growth hormone (GH) deficiency in adults results in many adverse changes similar to the changes which occur in humans with increasing age. The secretion of GH from the anterior pituitary declines with increasing age. This observation, together with the changes in body composition associated with organic GH deficiency in adults, has led to the suggestion that the elderly without hypothalamic-pituitary disease are GH deficient and may benefit from GH therapy. The impact of organic disease of the hypothalamic-pituitary axis in the elderly may result in a reduction in GH secretion of up to 90%. This reduction in GH secretion is sufficient to cause a fall in the serum insulin-like growth factor-1 (IGF-I) concentration, abnormal body composition and abnormal bone turnover, although bone mineral density is unaffected. These changes are distinct from those associated with the hyposomatotropism of the elderly, but are less severe than those seen in younger adults with organic GH deficiency. In this chapter we discuss the effects of organic GH deficiency in elderly subjects and the potential effects of GH replacement therapy. We also examine the potential for GH therapy to correct some of the detrimental effects of the ageing process. Key words: ageing; bone mineral density; body composition; growth hormone deficiency; growth hormone replacement; insulin-like growth factor-l.
GH deficiency is a frequent finding in adults with pituitary disease; indeed pituitary pathology must be present before the diagnosis can be made (Growth Hormone Research Society, 1998). GH deficiency in adults is characterized by changes in body composition (Salomon et al, 1989; Binnerts et al, 1992; Hoffman et al, 1995) and bone mineral density (Bing-You et al, * Address correspondence to: Dr Andrew Toogood, Departlnent of Internal Medicine, University of Virginia Health Sciences Center, Box 511, Charlottesville, Virginia, 22908, USA. Bailli~re ~ Clinical Endocrinology and Metabolism-
Vol. 12, No. 2, July 1998 ISBN 0-7020 2465-1 0950-351 X/98/020281 + 16 $12.00/00
281 Copyright 9 1998, by Bailli6re Tindall All rights of reproduction in any form reserved
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1993; Rosen et al, 1993a; Holmes et al, 1994), adverse changes in the serum lipid profile (Beshyah et al, 1944; de Boer et al, 1994), a reduction in exercise capacity (Cuneo et al, 1990) and abnormalities in cardiac function (Shahi et al, 1992; Merola et al, 1993). Current evidence suggests that patients with GH deficiency are at increased risk from cardiovascular disease and have a twofold increase in cardiovascular mortality (Rosen and Bengtsson, 1990). With increasing age the human body undergoes many physiological changes, a large proportion of which are detrimental and result in a decline in overall function (Forbes and Reina, 1970). There are considerable changes in body composition. Total body fat mass increases during adult life by 18% in men and 12% in women (Novak, 1972); this is due partly to an increasingly sedentary lifestyle. There is a tendency for increased central adiposity with increasing age. Fat-free tissue mass falls between the age of 25 and 70 years by approximately 27% in men and 15% in women. There is a decline in bone mineral density (Smith, 1967; Raisz, 1988), which becomes particularly pronounced in women who have become postmenopausal and are oestrogen deficient. Ageing is also associated with a decline in exercise capacity, adverse changes in the serum lipid profile, an increase in cardiovascular disease and, inevitably, a rising mortality rate. It is now well recognized that, following the peak in GH release during puberty, GH secretion in adults falls with increasing age (Carlson et al, 1972; Finkelstein et al, 1972; Dudl et al, 1973; Rudman et al, 1981; Ho et al, 1987; Iranmanesh et al, 1991; Veldhuis et al, 1991). This, together with the similarities between the changes which occur as a result of GH deficiency and those that occur with increasing age, has led some authors to suggest that a large proportion of healthy elderly individuals are GH deficient (Rudman, 1985). Studies of GH replacement therapy in GH-deficient adults have demonstrated beneficial effects on body composition (Salomon et al, 1989; Whitehead et al, 1989; Lonn et al, 1993; Holloway et al, 1994), bone mass (O'Halloran et al, 1993; Johannsson et al, 1996a), serum lipids (RussellJones et al, 1994; Beshyah et al, 1995b), cardiac function (Nass et al, 1995; Johannsson et al, 1996b) and quality of life. The majority of studies, however, have been performed in adults under the age of 60 years. Until recently, it was not known whether hypothalamic-pituitary disease in subjects over the age of 60 years caused a significant reduction in GH secretion, and, if it did, whether the resulting GH deficiency was sufficient to cause pathophysiological changes similar to those seen in younger GH deficient adults.
GH STATUS IN HEALTHY ELDERLY ADULTS The amount of GH released by the anterior pituitary gland is reduced in healthy elderly compared with healthy young adults (Finkelstein et al, 1972; Dudl et al, 1973; Rudman et al, 1981; Shibasaki et al, 1984; Zadik et al, 1985; Ho et al, 1987). Early studies reporting the changes that occur in GH secretion at various stages of adult life suggested that GH secretion
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ceased in the seventh decade of life (Finkelstein et al, 1972). The sensitivity of the GH assays used in these studies, however, was poor. Over the last 10 years the sensitivity of GH assays has increased; modern assays have a sensitivity of 0.002 gg/1 (Chapman et al, 1994). Using such assays to study physiological GH secretion with frequent sampling over 24 hours, it has become apparent that GH secretion continues throughout adult life. The amount of GH released from the anterior pituitary, however, gradually declines with increasing age, at a rate of approximately 14% per decade of adult life (Iranmanesh et al, 1991). What causes the age-related decline in GH secretion in adults? The amount of GH present in the anterior pituitary does not change with increasing age, and, using an appropriate stimulus, an elderly adult can produce a GH pulse similar to that seen in a younger adult (Ghigo et al, 1996; Toogood et al, 1998). The cause of the age-related fall in GH secretion may be attributed to changes in the secretion pattern of growth hormone-releasing hormone (GHRH) and somatostatin from the hypothalamus. GHRH stimulates the synthesis and release of GH from the anterior pituitary and is thought to determine the amplitude of a GH pulse. Somatostatin inhibits the release of GH from the anterior pituitary without affecting the synthesis of GH. The reduction of somatostatin secretion results in an increase in GH secretion and is the mechanism which determines the timing of GH pulses. There is evidence to suggest that a combination of declining GHRH action and increasing somatostatin tone causes the reduction in GH secretion associated with increasing age. In the elderly, the frequency of the GH pulses is the same as in young adults; however, the amplitude of the pulses is reduced (van Coevorden et al, 1991), suggesting that GHRH activity is reduced. The 'replacement' of GHRH by twice-daily injections or by continuous subcutaneous infusion in elderly subjects for 2 weeks increased spontaneous GH secretion and caused a rise in serum insulin-like growth factor-I (IGF-I) concentrations to levels seen in younger adults (Corpas et al, 1992a, 1993). Arginine is a GH secretagogue that is frequently used in the diagnosis of GH deficiency in adults and children. Arginine inhibits the secretion of somatostatin from the hypothalamus and induces a pulse of GH to be released. The GH response to arginine in healthy elderly adults is not significantly reduced compared with the GH response seen in healthy young adults (Toogood et al, 1998). When arginine and GHRH are administered together, a pronounced release of GH occurs which is not affected by the age of the subject (Ghigo et al, 1996). These observations indicate that the pool of GH available for release is not diminished in the elderly; GHRH activity is reduced in the elderly, but the increase in somatostatin tone is primarily responsible for the age associated decline in GH secretion. Recently it has become apparent that there is a third factor involved in the control of GH secretion from the anterior pituitary. It has been known for some time that a group of synthetic peptides, for example hexarelin and GHRP-6, and some non-peptide compounds, are potent GH secretagogues. Administration to elderly subjects results in a GH response in excess of that observed following GHRH (Arvat et al, 1994). The receptor for these
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compounds, the growth hormone-releasing substances (GHRS), has recently been identified (Howard et al, 1996), although the endogenous ligand remains unidentified. The receptor is found in the hypothalamus and in the anterior pituitary, suggesting that the GH-releasing substances regulate GHRH and somatostatin release from the hypothalamus and directly stimulate the somatotroph. Whether this addition to the GHRHGH-IGF-1 axis plays a significant role in the decline of GH secretion with increasing age remains to be seen. GH STATUS IN THE ELDERLY WITH HYPOTHALAMIC-PITUITARY DISEASE It has been suggested that adults over the age of 60 may be GH-deficient and may benefit from GH therapy. If this were the case one would not expect there to be a significant difference in GH secretion between healthy elderly subjects and elderly patients with hypothalamic-pituitary disease. The application of the new ultrasensitive GH assays now allows GH to be detected in serum in concentrations as low as 0.002 ~tg/1, which allows the accurate quantification of GH release in situations where it is known to be low, such as GH deficiency and the hyposomatotropism of ageing. In order to determine whether elderly patients with hypothalamicpituitary disease were significantly GH-deficient compared with their healthy peers, GH status was studied in 24 patients (16 male), aged 61-83 years, and 24 controls (17 male), aged 61-88 years (To ogood et al, 1996a). All the patients had developed their hypothalamic-pituitary disease in midto late life. The two groups had similar characteristics in terms of age and body mass index. All the subjects underwent a 24-hour GH profile, during which a blood sample was drawn every 20 minutes. The samples were initially analysed using a standard immunoradiometric assay (IRMA), the sensitivity of which was 0.4 ~tg/l. GH secretion in the patients was markedly reduced compared with the controls (area under the GH profile (AUC) < 9.6 (< 9.6-20) versus 18.5 (10.7-74.4) ~tg/1/24 hours, P<0.0001). In fact, 16 of the 24 patients failed to exhibit any detectable GH secretion throughout the 24-hour period. All the controls demonstrated a degree of GH secretion detectable in the IRMA at some point during the 24-hour profile. Of the eight patients who exhibited measurable GH secretion, one had apparently normal GH secretion, and in three of the remaining seven GH secretion fell into the lower part of the range seen in the controls. Despite this overlap, these data clearly demonstrate that the elderly with hypothalamic-pituitary disease have a reduction in GH secretion distinct from age related hyposomatotropism. In order to quantify the reduction in GH secretion all the samples were re-analysed using an ultrasensitive chemiluminescence assay, sensitivity 0.002 ~tg/1. In this assay GH concentrations were detectable in all the samples collected during each of the 48 growth hormone profiles. Using the ultrasensitive chemiluminescence assay it was possible to demonstrate that GH secretion in the elderly with hypothalamic-pituitary disease was
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reduced by 90% compared with healthy controls (Figure 1), thereby reinforcing the view that organic disease of the hypothalamic-pituitary axis results in GH deficiency that is distinct from the hyposomatotropism of ageing (Toogood et al, 1997c). 104
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Figure I. (A) Area under the curve (AUCGH) of the 24-hour GH profile measured using an ultrasensitive chemiluminesence assay, sensitivity 0.002 p.g/1, in 24 patients with hypothalamic-pituitary disease and 24 control subjects. P <0.00001. (B) GH response to an arginine stimulation test in the same subjects. P <0.00001. Horizontal bars represent medians.
DOES GH DEFICIENCY IN THE ELDERLY HAVE A SIGNIFICANT BIOLOGICAL IMPACT?
Having identified a significant reduction in GH secretion in the elderly with hypothalamic-pituitary disease it was important to determine whether it resulted in changes similar to those which occur in younger adults with GH deficiency. To this end we studied serological markers of GH function, IGF-1 and IGFBP-3, body composition and bone mineral density, utilizing dual-energy X-ray absorptiometry and markers of bone turnover. Serum IGF-1 and IGFBP-3
The serum concentrations of IGF-I and IGFBP-3 fall gradually with increasing age (Landin-Wilhelmsen et al, 1994; Ghigo et al, 1996). It is likely that the decline in IGF-1 and IGFBP-3 results, in part, from the agerelated decline in GH secretion. Because of this, serum IGF-1 and IGFBP-3 measurement must be evaluated in the context of age-specific normal-range data. Serum IGF-1 has been used as a marker of GH status with varying degrees of success. In young adults who had childhood-onset GH deficiency IGF-1 has been shown to be particularly useful; 93% showing an
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IGF-1 SDS below -2 (de Boer et al, 1995). In 65 GH-deficient adults, mean age 35 years, 70% had an IGF-1 SDS less than -2, a figure which may have been slightly inflated by the presence of patients with childhood-onset GH deficiency within the group (Holmes, 1995). In a study of adults, mean age 45 years, who had predominantly adult-onset GH deficiency, there was a considerable overlap between GH-deficient patients and controls, but 30% of the patients did have serum IGF- 1 concentrations below the range seen in healthy controls (Hoffman et al, 1994). In adults over the age of 60 years, although serum IGF-1 concentrations are significantly lower in GHdeficient subjects compared with controls, the overlap between the two groups is even greater. Only 17% of GH deficient subjects in our study had an IGF-1 concentration that fell below the age-specific normal range (Figure 2) (Toogood et al, 1998). Serum IGFBP-3 is the major binding protein for IGF-1 and is regulated by GH (Blum et al, 1990). The serum concentration of IGFBP-3 also falls with increasing age but to a lesser degree than IGF-1 and GH secretion (Donahue et al, 1990; Corpas et al, 1992b). IGFBP-3 concentrations in the elderly with pituitary disease were significantly lower than age-specific normal data; however, 96% of the patient values fell into the normal range (Figure 2) (Toogood et al, 1998). The reason for the considerable overlap of IGF-1 and IGFBP-3 between patients and controls is uncertain. In our own study we were unable to demonstrate a correlation between GH secretion and serum IGF-1 or IGFBP-3, confirming the findings of others (Corpas et al, 1992b). This suggests that, with increasing age, GH becomes a less important factor in the determination of the circulating IGF- 1 concentration. Other factors such as nutrition and chronic disease may assume a greater importance in regulating the production of IGF-1 and IGFBP-3 by the liver. 300
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Figure 2. Serum IGF-1 and IGFBP-3 levels in 24 GH-deficient patients compared with 127 healthy adults aged between 60 and 90 years of age. IGF-I : P <0.0001 ; IGFBP-3: P <0.009. Horizontal bars represent medians.
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Body
composition
GH defciency in young adults results in adverse changes in body composition with a rise in fat mass and a reduction in lean mass (Binnerts et al, 1992; Rosen et al, 1993b; Beshyah et al, 1995a). The distribution of fat mass is also abnormal, with an increase in central adiposity seen in those with GH deficiency (Weaver et al, 1995). Ageing is also associated with similar changes in body composition; there is a reduction in lean mass, an increase in fat mass and a change in the distribution of adipose tissue (Forbes and Reina, 1970; Novak, 1972). Computed tomography has shown a reduction in subcutaneous fat mass in the upper leg and a shift of abdominal fat from the subcutaneous region to the intra-abdominal cavity (Borkan et al, 1983). In the elderly with GH deficiency, evaluation of body composition by dual energy X-ray absorptiometry (DEXA) demonstrated a significant increase in fat mass (median [range] 27.50 [19.25-50.24])kg compared with the age matched controls (21.23 [8.81-49.15])kg (P=0.0047) (Toogood et al, 1996b). Lean mass, however, did not differ significantly between patients and controls. Dividing the DEXA scans into regions did not reveal any significant regional differences in fat distribution between the patients and controls (Table 1). However, the waist:hip ratio, a crude measure of central adiposity, was significantly increased in elderly GH-deficient patients. DEXA is limited when defining fat distribution as it cannot distinguish intra-abdominal visceral fat from subcutaneous fat. Thus it is possible that a higher proportion of visceral fat in the GH-deficient patients was missed through the limitation of the technique. Obesity per se is a cause of diminished GH secretion and, as expected, there was a significant negative correlation between fat mass and GH secretion in the controls (r = - 0 . 6 5 , P = 0.001). Such a relationship was not present in the patients, indicating that the increased fat mass observed in this group was not responsible for the reduction in GH secretion. Table 1. Total and regional body composition determined by DEXA in elderly patients with GH deficiency and healthy controls.
Total fat Total lean Arms fat Legs fat Trunk fat Arms lean Legs lean Trunk lean
Patients (kg)
Controls (kg)
P
27.499 19.245-50.243) 50.874 26.960-69.184)
21.233 (8.812-49.151) 51.551 (32.350-60.525)
0.0047
3.317 (1.994-8.283) 7.297 (4.232-16.381) 15.747 10.043-24.131) 6.706 (2.787 8.627) 16.168 (8.818-22.493) 24.356 12.491 35.223)
2.425 (0.777-7.102) 5.558 (2.397-17.057) 12.365 (5.132-23.237) 6.471 (3.506 8.060) 17.045 (10.58(/-21.002) 24.786 (15.252-29.868)
0.033
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0.021 0.(/09 09 0.4 0.96
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The fat-free mass determined by DEXA comprises cell mass and extracellular fluid; the former can be determined from estimates of total body potassium, the latter by various dilution techniques. Several studies have shown that there is a reduction in fat-free tissue in younger GH-deficient adults; however, Rosen et al (1993b) found that in GH-deficient adults over the age of 50 the reduction in body cell mass was no longer apparent. Thus it appears that the effects of GH deficiency on body composition are attenuated in the elderly, the major impact being on fat mass. Bone mineralization and bone turnover
The accrual of bone mineral takes place during adolescence and continues at a somewhat diminished rate during early adult life (Bonjour et al, 1991; Theintz et al, 1992). There is evidence to suggest that peak bone mass is reached during the third or even the early part of the fourth decade of life (Hall et al, 1990). Once peak bone mass has been attained there is a gradual decline in bone mineral with increasing age (Smith, 1967; Raisz, 1988). Adults who are GH-deficient have been shown to have a significant reduction in bone mineral density (BMD) compared with healthy agematched controls (Hyer et al, 1992; Rosen et al, 1993a; Holmes et al, 1994); indeed, this is currently considered to be one of the major indications for the provision of GH replacement therapy in adult life (Shalet, 1996). The severity of osteopenia appears to be related to the age of onset of GH deficiency. Patients with childhood-onset GH deficiency have more marked osteopenia (O'Halloran et al, 1993) compared with those who become GH deficient in adult life (Holmes et al, 1994). In our group of GH-deficient subjects over the age of 60 years, bone mineral density, determined by DEXA, was not significantly reduced at the hip or the lumbar spine compared with the controls (Table 2) (Toogood et al, 1997b). Similar findings have recently been reported by a group from Japan who studied slightly younger patients (mean age 52 years) (Kaji et al, 1997). Despite failing to demonstrate osteopenia in the elderly with GH deficiency, serum osteocalcin and urinary deoxypyridinoline X-links, Table 2. Bone mineral density, expressed as age-specific z-scores, and markers of bone formation and resorption in elderly patients with GH deficiency and healthy controls.
L2-L4 Femoral neck Femoral trochanter Ward's triangle Serum osteocalcin (p.g/1) Deoxypyridinoline X-link:creatinine (p.mol/mol)
Patients
Controls
P
0.80 (-2.83-2.95) 0.27 (-1.48-3.43) 0.46 (-2.14-3.37) 0.1 (-1.58-3.94) 11.5 (3.6-23.0) 3.5 (0.8-8.3)
1.10 (-2.87-2.64) 0.25 (-2.29-3.26) 0.5 (-2.4-3.8) 0.47 (-2.45-3.31) 15.1 (0.7-40.5) 4.9 (3.0-9.7)
0.68 0.89 0.98 0.96 0.019 0.038
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markers of bone formation and resorption, were reduced, suggesting a reduction in bone turnover (Table 2). In healthy elderly adults it has been shown that a reduction in bone turnover may actually protect against fractures (Garnero et al, 1996). Thus, rather than being at an increased risk of fracture as demonstrated in younger GH deficient adults, the elderly with organic GH deficiency may be protected from osteoporotic fractures. Further studies are required to determine whether the reduction in bone turnover observed in the elderly with GH deficiency, who have normal BMD, is of clinical significance, and whether GH replacement therapy in this age group modifies the risk of fracture.
DISTINGUISHING ORGANIC GH DEFICIENCY FROM AGE-RELATED HYPOSOMATOTROPISM The studies outlined above have demonstrated that the elderly with hypothalamic-pituitary disease have GH deficiency distinct from the agerelated decline in GH secretion. The reduction in GH secretion is sufficient to cause significant changes in serum IGF-1 concentrations, body composition and bone metabolism. The implication of these data is that the elderly with organic GH deficiency may benefit from GH replacement therapy. Studies in younger adults with hypothalamic-pituitary disease have shown that those who perceive the greatest benefit from GH replacement are those with more severe GH deficiency (Holmes et al, 1995). In the elderly, in whom the effects of GH deficiency appear to be attenuated, it is likely that only those with very severe GH deficiency will perceive any degree of benefit from GH replacement therapy. Such patients need to be identified effectively and safely. We have already seen that the degree of overlap observed in serum concentrations of IGF-1 and IGFBP-3 between patients and controls is considerable and excludes both as markers of GH deficiency in the elderly. Even assessment of spontaneous GH secretion failed to separate patients from controls; furthermore, the 24-hour profile is not a pragmatic method of defining GH status for routine clinical practice. Currently the most effective method of distinguishing GH deficiency from normality is a dynamic test of GH status (Shalet et al, 1998). The test most frequently quoted in the literature as the 'gold standard' is the insulin tolerance test (ITT) (Hoffman et al, 1994; Toogood et al, 1994), although other tests are being developed which may supercede the ITT (Ghigo et al, 1996). The ITT is potentially hazardous in the elderly who may have clinical or subclinical ischaemic heart disease. The arginine stimulation test (AST) is an alternative provocation test, although arginine is not as potent a secretagogue as the ITT (Rahim et al, 1996). The GH response to arginine is not influenced by age; side-effects of arginine infusion are limited to mild dizziness, and it appears to be much safer in the elderly, including those with overt ischaemic heart disease. For these reasons we chose the AST to study stimulated GH secretion in the elderly (Toogood et al, 1998).
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There was an excellent correlation between spontaneous GH secretion and the stimulated GH peak in both patients with hypothalamic-pituitary disease (r=0.89, P<0.0001) and healthy controls (r=0.56, P=0.005). Figure 1 demonstrates, however, that the AST was not able completely to separate patients from controls. The lowest GH peak in the controls was 1.8 g/l. If a peak GH value of less than 1.5 [tg/l is used as the diagnostic threshold for GH deficiency then the sensitivity of the AST is 77% with a specificity of 100%. If the three patients with isolated GH deficiency are excluded, the sensitivity of the AST rises to 86%. We have, therefore, suggested that a GH peak of 1.5 ~tg/1 be used to indicate impaired GH secretion in patients over the age of 60 years, We have previously demonstrated that the severity of GH deficiency increases as the number of anterior pituitary hormone deficits increases. Some 90% of patients with two or three hormone deficiencies, in addition to GH, had a GH peak to an ITT less than 2 ~tg/1 (Toogood et al, 1994). In the elderly, using similar methods, 89% of the patients with two or three additional anterior pituitary hormone deficits had a GH peak response to arginine less than 0.8 j.tg/1 (1 gg/1 = 2.6 mU/1), a level consistent with severe GH deficiency (Toogood et al, 1998).
GH replacement therapy in the elderly with organic hypothalamic-pituitary disease The majority of the studies of GH replacement therapy in adults have been limited to patients under the age of 60 years, GH deficiency in this age group does cause significant abnormalities that appear to be reduced in severity compared with the effects observed in younger adults. Despite this attenuation, it is possible that the elderly with organic GH deficiency will gain benefit from GH replacement therapy. The dose of GH replacement in GH deficient adults who are over 60 years old is lower than that used in younger patients. We recently completed a dose-finding study in the elderly with organic GH deficiency which examined the effects of three doses, 0.17, 0.33 and 0.5mg per day (1 r a g - 3 IU) of GH therapy on serum markers. One of the stated aims of GH therapy is to maintain the serum IGF-1 within the normal range (Growth Hormone Research Society, 1998). In our study, 0,5 mg of GH per day, administered subcutaneously at night, elevated the serum IGF-1 concentration above the age-specific normal range in 50% of subjects. At this dose three patients developed side-effects, requiring a dose reduction in two of them. A dose of 0.33 mg/day resulted in an IGF-1 concentration in the upper part of the normal range in all subjects and was not associated with side-effects. This replacement dose is considerably less than that used in younger adult patients with GH deficiency. During the study we assessed the effects of GH replacement therapy on body composition using DEXA, and quality of life using a diseasespecific questionnaire (Holmes et al, 1995). There was a significant fall in fat mass and also an increase in lean body mass. The quality of life data were difficult to interpret as they were confounded by the age of the
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patients and the design of the study. Using a disease-specific validated questionnaire we were, however, able to demonstrate a significant improvement in quality of life after 6 months of GH replacement therapy (Toogood et al, 1997a). This study provides evidence that the elderly with organic GH deficiency derive benefit from GH replacement in the short term. Further studies are required to determine whether these changes persist.
GH therapy in healthy elderly subjects Ageing is associated with a fall in GH secretion and physiological changes similar to those observed in younger adults who have organic GH deficiency. The beneficial effects of GH replacement reported in patients with organic GH deficiency led to the suggestion that GH treatment in the elderly would improve body composition, BMD and muscle strength. One early study used GH to increase the serum IGF-1 of healthy men into the range observed in adults in their twenties (Rudman et al, 1990). Over a 6-month period, GH therapy resulted in an increase in lean mass, a decrease in fat mass and a significant rise in vertebral BMD. Despite the significant gains in muscle mass observed with GH therapy, actual muscle strength did not improve (Taafe et al, 1994). The increase in BMD observed in adults who received GH replacement therapy for organic GH deficiency suggested that it may be useful in the management of primary osteoporosis. Unfortunately the gains in BMD are similar to those seen with less expensive anti-resorptive compounds, such as the bisphosphonates, which can be taken orally (Marcus et al, 1993). Side-effects of GH therapy were common in elderly subjects who received it in studies aiming to reverse the hyposomatotropism of age. Subjects frequently required dose reduction, or were withdrawn from the study, when they developed oedema, carpal tunnel syndrome and occasionally gynaecomastia (Cohn et al, 1993; Holloway et al, 1994; Taafe et al, 1994). The high incidence of side-effects in elderly subjects who do not have organic GH deficiency limits the use of GH therapy considerably. At the present time, there are no data on the long-term effects, beneficial or otherwise, of GH therapy given to healthy elderly subjects. In a recent study the potential dangers that may be associated with artificially increasing the serum IGF-1 concentration were illustrated. Chan et al (1998) found a strong correlation between serum IGF-1 concentrations and the risk of developing prostate cancer. Subjects taking part in the Physicians' Health Study who developed prostate cancer had significantly higher serum IGF-1 concentrations at enrollment into the study compared with age-matched controls. The relationship between the relative risk of developing prostate cancer and serum IGF-1 concentration was particularly pronounced in men over 60 years of age. This study serves to emphasize that great caution is required before long-term GH therapy is offered to the normal elderly.
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CONCLUSIONS The decline in growth hormone secretion associated with increasing age runs in parallel with the changes in body composition, reduction in muscle strength and BMD which occur as we grow older. Hypothalamic-pituitary disease in the elderly results in a highly significant reduction in GH secretion compared with healthy age-matched controls. Although this degree of GH deficiency is sufficient to cause a reduction in serum IGF-1 and abnormalities of body composition, the severity of the changes are greatly attenuated compared to the changes observed in younger adults who have GH deficiency. A study of GH replacement therapy in patients over the age of 60 years who have organic GH deficiency resulted in a rise in serum IGF-1 concentration and changes in body composition, and suggested that these patients do receive some benefit in terms of improved quality of life. GH therapy used in adults who did not have organic disease of the hypothalamicpituitary axis resulted in a high incidence of side-effects, and, although lean body mass increased and fat mass fell, did not cause a significant improvement in muscle strength. The biological changes associated with 90% reduction in GH secretion caused by organic disease of the hypothalamic-pituitary axis in the elderly are greatly attenuated compared with the effects observed in younger adults. This suggests that the decline in GH with increasing age does not play a major role in the ageing changes that affect body composition and the skeleton. This, together with the recent findings that serum IGF-1 concentrations in the upper rather than lower part of the normal range increase the risk of prostate cancer, suggests that GH therapy is not appropriate in the elderly who do not have organic GH deficiency. We should also be cautious in the use of GH in those elderly patients with organic disease of the hypothalamic-pituitary axis, and ensure careful monitoring to keep the IGF-1 level within the normal range.
REFERENCES Arvat E, Gianotti L, Grottoli Set al (1994) Arginine and growth hormone-releasing hormone restore the blunted growth hormone-releasing activity of hexarelin in elderly subjects. Journal of Clinical Endocrinology and Metabolism 79: 1440-1443. Beshyah SA, Henderson A, Niththyanathan R et al (1994) Metabolic abnormalities in growth hormone deficient adults: carbohydrate tolerance and lipid metabolism. Endocrinology and Metabolism 1: I73-I80. Beshyah SA, Freemantle C, Thomas E et al (1995a) Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults. Clinical Endocrinology 42: 179-189. Beshyah SA, Henderson A, Niththyanathan R et al (1995b) The effects of short and long term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate metabolism. Journal ~f Clinical Endocrinology and Metabolism 80: 356-363. Bing-You RG, Denis M-C & Rosen CJ (1993) Low bone mineral density in adults with previous hypothalamic-pituitary tumors: correlations with serum growth hormone responses to GHreleasing hormone, insulin-like growth factor I, and IGF binding protein 3. Calcified Tisstte International 52: 183-187.
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Binnerts A, Deurenberg R Swart GR et al (1992) Body composition in growth hormone-deficient adults. American Journal of Clinical Nutrition 55:918-923. Blum WF, Ranke MB, Kietzmann K et al (1990) A specific radioimmunoassay for the growth hormone-dependent somatomedin-binding protein: its use for diagnosis of growth hormone deficiency. Journal ~?['CIinical Endocrinology and Metabolism 70: 1292-1298. de Boer H, Blok GJ, Voerman HJ et al (1994) Serum lipid levels in growth hormone deficient men. Metabolism 43:199-203. *de Boer H, Blok G-J & van der Veen EA (1995) Clinical aspects of growth hormone deficiency in adults. Endocrine Reviews 16: 63-86. Bonjour J-P, Theintz G, Buchs B e t al (1991) Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. Journal ~?f Clinical Endocrinology and Metabolism 73: 555-563. Borkan GA, Hults DE, Gerzof SG et al (1983) Age related changes in body composition revealed by computed tomography. Journal ~f Gerontology 38: 673-677. Carlson HE, Gillin JC, Gorden P & Snyder F (1972) Absence of sleep related growth hormone peaks in aged normal subjects and in acromegaly. Journal of Clinical Endocrinology and Metabolism 34: 1102-1105. *Chan J, Stampfer M, Giovannucci E et al (1998) Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279: 563-566. Chapman IM, Hartman ML, Straume M e t al (1994) Enhanced sensitivity growth hormone chemiluminescence assay reveals lower postglucose nadir GH concentrations in men than women. Journal r Clinical Endocrinology and Metabolism 78: 1312-1319. van Coevorden A, Mockel J, Laurent E et al ( 1991) Neuroendocrine rhythms and sleep in aging men. American Journal o[ Physiology 260:E651 -E661. Cohn L, Feller AG, Draper MW et al (1993) Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations. Clinical Endocrinology 39:417-425. Corpas E, Harman SM, Pineyro MA et al (1992a) Growth hormone (GH)-releasing hormone-(l-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. Journal of Clinical Endocrinology and Metabolism 75: 530-535. Corpas E, Harman SM & Blackman MR (1992b) Serum IGF-binding protein-3 is related to IGF-I, but not to spontaneous GH release, in healthy old men. Hormone and Metabolism Research 24: 543-545. Corpas E, Harman SM, Pineyro MA et al (1993) Continuous subcutaneous infusions of growth hormone (GH) releasing hormone 1-44 for 14 days increase GH and insulin-like growth factor-I levels in old men. Journal of Clinical Endocrinology and Metabolism 76: 134-138. Cuneo RC, Salomon F, Wiles CM & S6nksen PH (1990) Skeletal muscle performance in adults with growth hormone deficiency. Hormone Research 33 (supplement 4): 55-60. Donahue LR, Hunter SJ, Sherblom AP & Rosen C (1990) Age related changes in serum insulin-like growth factor-binding proteins in women. Journal ~["Clinical Endocrinology and Metabolism 71: 575-579. Dudl R J, Ensinck JW, Palmer HE & Williams RH (1973) Effect of age on growth hormone secretion in man. Journal ~1~Clinical Endocrinology and Metabolism 37:11 - 16. Finkelstein JW, Roffwarg HI:', Boyar RM et al (1972) Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. Journal of Clinical Endocrinology and Metabolism 35: 665-670. Forbes GB & Reina JC (1970) Adult lean body mass declines with age: some longitudinal observations. Metabolism 19: 653-663. Gamero E Somay-Rendu E, Chapuy M-C & Delmas PD (1996) Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. Journal ~?f Bone and Mineral Research 11: 337-349. Ghigo E, Aimaretti G, Gianotti L et al (1996) New approach to the diagnosis of growth hormone deficiency in adults. European Journal e)(Endocrinology 134: 352-356. *Growth Hormone Research Society (1998) Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society workshop on adult growth hormone deficiency. Journal c~f Clinical Endocrinology and Metabolism 83:379-381. Hall ML, Heavens J, Cullum ID & Ell PJ (1990) The range of bone density in normal British women. British Journal Radiology 63: 266-269.
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Ho KY, Evans WS, Blizzard RM et al (1987) Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. Journal of Clinical Endocrinology and Metabolism 64:51-58. Hoffman DM, O'Sullivan A J, Baxter RC & Ho KKY (1994) Diagnosis of growth hormone deficiency in adults. Lancet 343: 1064-1068. Hoffman DM, O'Sullivan A J, Freund J & Ho KK (I995) Adults with growth hormone deficiency have abnormal body composition but normal energy metabolism. Journal of Clinical Endocrinology and Metabolism 80: 72-77. Holloway L, Butterfield G, Hintz RL et al (1994) Effects of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women~ Journal of Clinical Endocrinology and Metabolism 79: 470-479. Holmes SJ (1995) Growth hormone replacement in adults with growth hormone deficiency. Thesis, University of London, 286 pp. Holmes SJ & Shalet SM (1995) Factors influencing the desire for long term growth hormone replacement in adults. Clinical Endocrinology 43: 151-157. Holmes S J, Economou G, Whitehouse RW et al (1994) Reduced bone mineral density in patients with adult onset growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 78: 669-674. Holmes SJ, McKenna SP, Doward LC et al (1995) Development of a questionnaire to assess the quality of life of adults with growth hormone deficiency. Endocrinology and Metabolism 2: 63 -69. Howard AD, Feighner SD, Cully DF et al (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273: 974-977. Hyer SL, Rodin DA, Tobias JH et al (1992) Growth hormone deficiency during puberty reduces adult bone mineral density. Archives of Disease in Childhood 67: 1472-1474. *lranmanesh A, Lizarralde GB, Veldhuis JD (1991) Age and relative obesity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. Journal of Clinical Endocrinology and Metabolism 73: 1081-1088. Johannsson G, Rosen T, Bosaeus 1 et al (1996a) Long term growth hormone treatment increases bone mineral content and density in patients with adult-onset growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 81: 2865-2873. Johannsson G, Bengtsson B-Y, Andersson Bet al (1996b) Long term cardiovascular effects of growth hormone treatment in GH-deficient adults: preliminary data in a small group of patients. Clinical Endocrinology 45:305-314. Kaji H, Abe H, Fukase M & Chihara K (1997) Normal bone mineral density in patients with adult onset GH deficiency. Endocrinology and Metabolism 4:163-166. Landin-Withelmsen K, Wilhelmsen L, Lappas Get al (1994) Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clinical Endocrinology 41:351-357. Lonn L, Kvist H, Grangard U et al (1993) CT-determined body composition changes with recombinant human growth hormone treatment to adults with growth hormone deficiency. Basic Life Sciences 60: 229-231. *Marcus R, Holloway L & Butterfield G (1993) Clinical uses of growth hormone in older people. Journal of Reproduction and Fertility 46 (supplement): 115-118. Merola B, Cittadini A, Colao A et al (1993) Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 77: 1658-1661. Nass R, Huber RM, Klauss Vet al (1995) Effect of growth hormone replacement therapy on physical work capacity and cardiac and pulmonary function in patients with hGH deficiency acquired in adulthood. Journal of Clinical Endocrinology and Metabolism 80: 552-557. Novak LP (1972) Aging, total body potassium, fat-free mass and cell mass in males and females between ages 18 and 85. Journal of Gerontology 27: 439-443. O'Halloran DJ, Tsatsoulis A, Whitchouse RW et al (1993) Increased bone density after recombinant human growth hormone therapy in adults with isolated GH deficiency. Journal of Clinical Endocrinology and Metabolism 76: 1344-1348. Rahim A, Toogood AA & Shalet SM (1996) The assessment of growth hormone status in normal young adult males using a variety of provocative tests. Clinical Endocrinology 45: 557-562.
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Raisz LG (1988) Local and systemic factors in the pathogenesis of osteoporosis. New England Journal of Medicine 318" 818-828. Rosen T & Bengtsson B (1990) Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336: 285-288. Rosen T, Hansson T, Granhed H et al (1993a) Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinologica 129" 201-206. Rosen T, Bosaeus 1, TOlli J e t al (1993b) Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clinical Endocrinology 3 8 : 6 3 - 7 1 . Rudman D (1985) Growth hormone, body composition and aging. Journal of the American Geriatric Socie(~' 33: 800-807. *Rudman D, Kutner MH, Rogers CM et al (1981) Impaired growth hormone secretion in the adult population: Relation to age and adiposity. Journal qf Clinical Investigation 67: 13611369. *Rudman D, Feller AG, Nagraj HS et al (1990) Effects of human growth hormone in men over 60 years old. New England Journal ~f Medicine 3 2 3 : 1 - 6 . Russell-Jones DL, Watts GF, Weissberger AJ et al (1994) The effect of growth hormone replacement on serum lipids, lipoproteins and cholesterol precursors in adult growth hormone deficient patients. Clinical Endocrinology 41: 345-350. Salomon F, Cuneo RC, Hesp R & S6nksen PH (1989) The effects of treatment with recombinant human growth hormone on body composition in adults with growth hormone deficiency. New England Journal ~f Medicine 321: 1797-1803. Shahi M, Beshyah SA, Hackett D et al (1992) Myocardial dysfunction in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality. British Heart Journal 67: 92-96. Shalet SM (1996) Growth hormone deficiency and replacement in adults. British Medical Journal 313: 314. Shalet SM, Toogood AA, Rahim A & Brennan BMD (1998) The diagnosis of growth hormone deficiency in children and adults. Endocrine Reviews 19: 203-223. Shibasaki T, Shizume K, Nakahara M e t al (1984) Age related changes in plasma growth hormone response to growth hormone releasing factor in man. Journal c~f Clinical Endocrinology and Metabolism 58: 212-214. Smith RW Jr (1967) Dietary and hormonal factors in bone loss. Federation Proceedings 26: 1737 1746. Taafe DR, Pruitt L, Reim Jet al (1994) Effect of recombinant human growth hormone on the nmscle strength response to resistance exercise in elderly men. Journal qf Clinical Endocrinology and Metabolism 79:1361 - 1366. Theintz G, Buchs B, Rizzoli R et al (1992) Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. Journal qf Clinical Endocrinology and Metabolism 75: 1060-1(/65. Toogood AA, Beardwell CG & Shalet SM (1994) The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clinical Endocrinology 41: 511-516. *Toogood AA, O'Neill PA & Shalet SM (1996a) Beyond the somatopause: growth hormone deficiency in adults over the age of 60 years. Journal qf Clinical Endocrinology attd Metabolism 81: 460 465. *Toogood AA, Adams JE, O'Neill PA & Shalet SM (1996b) Body composition in growth hormone deficient adults over the age of 60 years. Clinical Endocrinology 45: 399-405. Toogood A, Wieringa G, Adams J & Shalet S (1997a) Growth hormone replacement therapy in the elderly with organic growth hormone deficiency: do they benefit? 79th Annual Meeting of the Endocrine Society, Minneapolis, 1997. *Toogood AA, Adams JE, O'Neill PA & Shalet SM (1997b) Elderly patients with adult onset growth hormone deticiency are not osteopenic. Journal qf Clinical Endocrinology and Metabolism 82: 1462-1466. Toogood AA, Nass RM, Pezzoli SS et al (1997c) Preservation of growth hormone pulsatility despite pituitary pathology, surgery and irradiation. Journal ~["Clinical Endocrinology and Metabolism 82: 2215-2221. Toogood A, Jones J, O'Neill P et al (1998) The diagnosis of severe growth hormone deficiency in elderly patients with hypothalamic-pituitary disease. Clinical Endocrinology 48: 569-576.
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Veldhuis JD, Iranmanesh A, Ho KKY et al ( 1991) Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatropism of obesity in man. Journal of Clinical Endocrinology and Metabolism 72:51-59. Weaver JU, Monson JP, Noonan K et al (1995) The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity and cardiovascular risk factors in hypopituitary adults. Journal of Clinical Endocrinology and Metabolism 80:153-159. Whitehead HM, Gilliland JS, Allen IV & Hadden DR (1989) Growth hormone treatment in adults with growth hormone deficiency: effect on muscle fibre size and proportions. Acta Paediatrica 356 (supplement): 65-67. Zadik Z, Chalew SA, McCarter RJ et al (1985) The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. Journal of Clinical Endocrinology and Metabolism 60: 513-516.
S T E P H E N M. S H A L E T MD, FRCP Professor of Endocrinology Department (~{Endocrinology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester; M20 4BX, UK
Organic growth hormone (GH) deficiency in adults results in many adverse changes similar to the changes which occur in humans with increasing age. The secretion of GH from the anterior pituitary declines with increasing age. This observation, together with the changes in body composition associated with organic GH deficiency in adults, has led to the suggestion that the elderly without hypothalamic-pituitary disease are GH deficient and may benefit from GH therapy. The impact of organic disease of the hypothalamic-pituitary axis in the elderly may result in a reduction in GH secretion of up to 90%. This reduction in GH secretion is sufficient to cause a fall in the serum insulin-like growth factor-1 (IGF-I) concentration, abnormal body composition and abnormal bone turnover, although bone mineral density is unaffected. These changes are distinct from those associated with the hyposomatotropism of the elderly, but are less severe than those seen in younger adults with organic GH deficiency. In this chapter we discuss the effects of organic GH deficiency in elderly subjects and the potential effects of GH replacement therapy. We also examine the potential for GH therapy to correct some of the detrimental effects of the ageing process. Key words: ageing; bone mineral density; body composition; growth hormone deficiency; growth hormone replacement; insulin-like growth factor-l.
GH deficiency is a frequent finding in adults with pituitary disease; indeed pituitary pathology must be present before the diagnosis can be made (Growth Hormone Research Society, 1998). GH deficiency in adults is characterized by changes in body composition (Salomon et al, 1989; Binnerts et al, 1992; Hoffman et al, 1995) and bone mineral density (Bing-You et al, * Address correspondence to: Dr Andrew Toogood, Departlnent of Internal Medicine, University of Virginia Health Sciences Center, Box 511, Charlottesville, Virginia, 22908, USA. Bailli~re ~ Clinical Endocrinology and Metabolism-
Vol. 12, No. 2, July 1998 ISBN 0-7020 2465-1 0950-351 X/98/020281 + 16 $12.00/00
281 Copyright 9 1998, by Bailli6re Tindall All rights of reproduction in any form reserved
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1993; Rosen et al, 1993a; Holmes et al, 1994), adverse changes in the serum lipid profile (Beshyah et al, 1944; de Boer et al, 1994), a reduction in exercise capacity (Cuneo et al, 1990) and abnormalities in cardiac function (Shahi et al, 1992; Merola et al, 1993). Current evidence suggests that patients with GH deficiency are at increased risk from cardiovascular disease and have a twofold increase in cardiovascular mortality (Rosen and Bengtsson, 1990). With increasing age the human body undergoes many physiological changes, a large proportion of which are detrimental and result in a decline in overall function (Forbes and Reina, 1970). There are considerable changes in body composition. Total body fat mass increases during adult life by 18% in men and 12% in women (Novak, 1972); this is due partly to an increasingly sedentary lifestyle. There is a tendency for increased central adiposity with increasing age. Fat-free tissue mass falls between the age of 25 and 70 years by approximately 27% in men and 15% in women. There is a decline in bone mineral density (Smith, 1967; Raisz, 1988), which becomes particularly pronounced in women who have become postmenopausal and are oestrogen deficient. Ageing is also associated with a decline in exercise capacity, adverse changes in the serum lipid profile, an increase in cardiovascular disease and, inevitably, a rising mortality rate. It is now well recognized that, following the peak in GH release during puberty, GH secretion in adults falls with increasing age (Carlson et al, 1972; Finkelstein et al, 1972; Dudl et al, 1973; Rudman et al, 1981; Ho et al, 1987; Iranmanesh et al, 1991; Veldhuis et al, 1991). This, together with the similarities between the changes which occur as a result of GH deficiency and those that occur with increasing age, has led some authors to suggest that a large proportion of healthy elderly individuals are GH deficient (Rudman, 1985). Studies of GH replacement therapy in GH-deficient adults have demonstrated beneficial effects on body composition (Salomon et al, 1989; Whitehead et al, 1989; Lonn et al, 1993; Holloway et al, 1994), bone mass (O'Halloran et al, 1993; Johannsson et al, 1996a), serum lipids (RussellJones et al, 1994; Beshyah et al, 1995b), cardiac function (Nass et al, 1995; Johannsson et al, 1996b) and quality of life. The majority of studies, however, have been performed in adults under the age of 60 years. Until recently, it was not known whether hypothalamic-pituitary disease in subjects over the age of 60 years caused a significant reduction in GH secretion, and, if it did, whether the resulting GH deficiency was sufficient to cause pathophysiological changes similar to those seen in younger GH deficient adults.
GH STATUS IN HEALTHY ELDERLY ADULTS The amount of GH released by the anterior pituitary gland is reduced in healthy elderly compared with healthy young adults (Finkelstein et al, 1972; Dudl et al, 1973; Rudman et al, 1981; Shibasaki et al, 1984; Zadik et al, 1985; Ho et al, 1987). Early studies reporting the changes that occur in GH secretion at various stages of adult life suggested that GH secretion
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ceased in the seventh decade of life (Finkelstein et al, 1972). The sensitivity of the GH assays used in these studies, however, was poor. Over the last 10 years the sensitivity of GH assays has increased; modern assays have a sensitivity of 0.002 gg/1 (Chapman et al, 1994). Using such assays to study physiological GH secretion with frequent sampling over 24 hours, it has become apparent that GH secretion continues throughout adult life. The amount of GH released from the anterior pituitary, however, gradually declines with increasing age, at a rate of approximately 14% per decade of adult life (Iranmanesh et al, 1991). What causes the age-related decline in GH secretion in adults? The amount of GH present in the anterior pituitary does not change with increasing age, and, using an appropriate stimulus, an elderly adult can produce a GH pulse similar to that seen in a younger adult (Ghigo et al, 1996; Toogood et al, 1998). The cause of the age-related fall in GH secretion may be attributed to changes in the secretion pattern of growth hormone-releasing hormone (GHRH) and somatostatin from the hypothalamus. GHRH stimulates the synthesis and release of GH from the anterior pituitary and is thought to determine the amplitude of a GH pulse. Somatostatin inhibits the release of GH from the anterior pituitary without affecting the synthesis of GH. The reduction of somatostatin secretion results in an increase in GH secretion and is the mechanism which determines the timing of GH pulses. There is evidence to suggest that a combination of declining GHRH action and increasing somatostatin tone causes the reduction in GH secretion associated with increasing age. In the elderly, the frequency of the GH pulses is the same as in young adults; however, the amplitude of the pulses is reduced (van Coevorden et al, 1991), suggesting that GHRH activity is reduced. The 'replacement' of GHRH by twice-daily injections or by continuous subcutaneous infusion in elderly subjects for 2 weeks increased spontaneous GH secretion and caused a rise in serum insulin-like growth factor-I (IGF-I) concentrations to levels seen in younger adults (Corpas et al, 1992a, 1993). Arginine is a GH secretagogue that is frequently used in the diagnosis of GH deficiency in adults and children. Arginine inhibits the secretion of somatostatin from the hypothalamus and induces a pulse of GH to be released. The GH response to arginine in healthy elderly adults is not significantly reduced compared with the GH response seen in healthy young adults (Toogood et al, 1998). When arginine and GHRH are administered together, a pronounced release of GH occurs which is not affected by the age of the subject (Ghigo et al, 1996). These observations indicate that the pool of GH available for release is not diminished in the elderly; GHRH activity is reduced in the elderly, but the increase in somatostatin tone is primarily responsible for the age associated decline in GH secretion. Recently it has become apparent that there is a third factor involved in the control of GH secretion from the anterior pituitary. It has been known for some time that a group of synthetic peptides, for example hexarelin and GHRP-6, and some non-peptide compounds, are potent GH secretagogues. Administration to elderly subjects results in a GH response in excess of that observed following GHRH (Arvat et al, 1994). The receptor for these
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compounds, the growth hormone-releasing substances (GHRS), has recently been identified (Howard et al, 1996), although the endogenous ligand remains unidentified. The receptor is found in the hypothalamus and in the anterior pituitary, suggesting that the GH-releasing substances regulate GHRH and somatostatin release from the hypothalamus and directly stimulate the somatotroph. Whether this addition to the GHRHGH-IGF-1 axis plays a significant role in the decline of GH secretion with increasing age remains to be seen. GH STATUS IN THE ELDERLY WITH HYPOTHALAMIC-PITUITARY DISEASE It has been suggested that adults over the age of 60 may be GH-deficient and may benefit from GH therapy. If this were the case one would not expect there to be a significant difference in GH secretion between healthy elderly subjects and elderly patients with hypothalamic-pituitary disease. The application of the new ultrasensitive GH assays now allows GH to be detected in serum in concentrations as low as 0.002 ~tg/1, which allows the accurate quantification of GH release in situations where it is known to be low, such as GH deficiency and the hyposomatotropism of ageing. In order to determine whether elderly patients with hypothalamicpituitary disease were significantly GH-deficient compared with their healthy peers, GH status was studied in 24 patients (16 male), aged 61-83 years, and 24 controls (17 male), aged 61-88 years (To ogood et al, 1996a). All the patients had developed their hypothalamic-pituitary disease in midto late life. The two groups had similar characteristics in terms of age and body mass index. All the subjects underwent a 24-hour GH profile, during which a blood sample was drawn every 20 minutes. The samples were initially analysed using a standard immunoradiometric assay (IRMA), the sensitivity of which was 0.4 ~tg/l. GH secretion in the patients was markedly reduced compared with the controls (area under the GH profile (AUC) < 9.6 (< 9.6-20) versus 18.5 (10.7-74.4) ~tg/1/24 hours, P<0.0001). In fact, 16 of the 24 patients failed to exhibit any detectable GH secretion throughout the 24-hour period. All the controls demonstrated a degree of GH secretion detectable in the IRMA at some point during the 24-hour profile. Of the eight patients who exhibited measurable GH secretion, one had apparently normal GH secretion, and in three of the remaining seven GH secretion fell into the lower part of the range seen in the controls. Despite this overlap, these data clearly demonstrate that the elderly with hypothalamic-pituitary disease have a reduction in GH secretion distinct from age related hyposomatotropism. In order to quantify the reduction in GH secretion all the samples were re-analysed using an ultrasensitive chemiluminescence assay, sensitivity 0.002 ~tg/1. In this assay GH concentrations were detectable in all the samples collected during each of the 48 growth hormone profiles. Using the ultrasensitive chemiluminescence assay it was possible to demonstrate that GH secretion in the elderly with hypothalamic-pituitary disease was
285
AGEING AND GROWTH HORMONE STATUS
reduced by 90% compared with healthy controls (Figure 1), thereby reinforcing the view that organic disease of the hypothalamic-pituitary axis results in GH deficiency that is distinct from the hyposomatotropism of ageing (Toogood et al, 1997c). 104
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Figure I. (A) Area under the curve (AUCGH) of the 24-hour GH profile measured using an ultrasensitive chemiluminesence assay, sensitivity 0.002 p.g/1, in 24 patients with hypothalamic-pituitary disease and 24 control subjects. P <0.00001. (B) GH response to an arginine stimulation test in the same subjects. P <0.00001. Horizontal bars represent medians.
DOES GH DEFICIENCY IN THE ELDERLY HAVE A SIGNIFICANT BIOLOGICAL IMPACT?
Having identified a significant reduction in GH secretion in the elderly with hypothalamic-pituitary disease it was important to determine whether it resulted in changes similar to those which occur in younger adults with GH deficiency. To this end we studied serological markers of GH function, IGF-1 and IGFBP-3, body composition and bone mineral density, utilizing dual-energy X-ray absorptiometry and markers of bone turnover. Serum IGF-1 and IGFBP-3
The serum concentrations of IGF-I and IGFBP-3 fall gradually with increasing age (Landin-Wilhelmsen et al, 1994; Ghigo et al, 1996). It is likely that the decline in IGF-1 and IGFBP-3 results, in part, from the agerelated decline in GH secretion. Because of this, serum IGF-1 and IGFBP-3 measurement must be evaluated in the context of age-specific normal-range data. Serum IGF-1 has been used as a marker of GH status with varying degrees of success. In young adults who had childhood-onset GH deficiency IGF-1 has been shown to be particularly useful; 93% showing an
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IGF-1 SDS below -2 (de Boer et al, 1995). In 65 GH-deficient adults, mean age 35 years, 70% had an IGF-1 SDS less than -2, a figure which may have been slightly inflated by the presence of patients with childhood-onset GH deficiency within the group (Holmes, 1995). In a study of adults, mean age 45 years, who had predominantly adult-onset GH deficiency, there was a considerable overlap between GH-deficient patients and controls, but 30% of the patients did have serum IGF- 1 concentrations below the range seen in healthy controls (Hoffman et al, 1994). In adults over the age of 60 years, although serum IGF-1 concentrations are significantly lower in GHdeficient subjects compared with controls, the overlap between the two groups is even greater. Only 17% of GH deficient subjects in our study had an IGF-1 concentration that fell below the age-specific normal range (Figure 2) (Toogood et al, 1998). Serum IGFBP-3 is the major binding protein for IGF-1 and is regulated by GH (Blum et al, 1990). The serum concentration of IGFBP-3 also falls with increasing age but to a lesser degree than IGF-1 and GH secretion (Donahue et al, 1990; Corpas et al, 1992b). IGFBP-3 concentrations in the elderly with pituitary disease were significantly lower than age-specific normal data; however, 96% of the patient values fell into the normal range (Figure 2) (Toogood et al, 1998). The reason for the considerable overlap of IGF-1 and IGFBP-3 between patients and controls is uncertain. In our own study we were unable to demonstrate a correlation between GH secretion and serum IGF-1 or IGFBP-3, confirming the findings of others (Corpas et al, 1992b). This suggests that, with increasing age, GH becomes a less important factor in the determination of the circulating IGF- 1 concentration. Other factors such as nutrition and chronic disease may assume a greater importance in regulating the production of IGF-1 and IGFBP-3 by the liver. 300
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Figure 2. Serum IGF-1 and IGFBP-3 levels in 24 GH-deficient patients compared with 127 healthy adults aged between 60 and 90 years of age. IGF-I : P <0.0001 ; IGFBP-3: P <0.009. Horizontal bars represent medians.
287
AGEING AND GROWTH HORMONE STATUS
Body
composition
GH defciency in young adults results in adverse changes in body composition with a rise in fat mass and a reduction in lean mass (Binnerts et al, 1992; Rosen et al, 1993b; Beshyah et al, 1995a). The distribution of fat mass is also abnormal, with an increase in central adiposity seen in those with GH deficiency (Weaver et al, 1995). Ageing is also associated with similar changes in body composition; there is a reduction in lean mass, an increase in fat mass and a change in the distribution of adipose tissue (Forbes and Reina, 1970; Novak, 1972). Computed tomography has shown a reduction in subcutaneous fat mass in the upper leg and a shift of abdominal fat from the subcutaneous region to the intra-abdominal cavity (Borkan et al, 1983). In the elderly with GH deficiency, evaluation of body composition by dual energy X-ray absorptiometry (DEXA) demonstrated a significant increase in fat mass (median [range] 27.50 [19.25-50.24])kg compared with the age matched controls (21.23 [8.81-49.15])kg (P=0.0047) (Toogood et al, 1996b). Lean mass, however, did not differ significantly between patients and controls. Dividing the DEXA scans into regions did not reveal any significant regional differences in fat distribution between the patients and controls (Table 1). However, the waist:hip ratio, a crude measure of central adiposity, was significantly increased in elderly GH-deficient patients. DEXA is limited when defining fat distribution as it cannot distinguish intra-abdominal visceral fat from subcutaneous fat. Thus it is possible that a higher proportion of visceral fat in the GH-deficient patients was missed through the limitation of the technique. Obesity per se is a cause of diminished GH secretion and, as expected, there was a significant negative correlation between fat mass and GH secretion in the controls (r = - 0 . 6 5 , P = 0.001). Such a relationship was not present in the patients, indicating that the increased fat mass observed in this group was not responsible for the reduction in GH secretion. Table 1. Total and regional body composition determined by DEXA in elderly patients with GH deficiency and healthy controls.
Total fat Total lean Arms fat Legs fat Trunk fat Arms lean Legs lean Trunk lean
Patients (kg)
Controls (kg)
P
27.499 19.245-50.243) 50.874 26.960-69.184)
21.233 (8.812-49.151) 51.551 (32.350-60.525)
0.0047
3.317 (1.994-8.283) 7.297 (4.232-16.381) 15.747 10.043-24.131) 6.706 (2.787 8.627) 16.168 (8.818-22.493) 24.356 12.491 35.223)
2.425 (0.777-7.102) 5.558 (2.397-17.057) 12.365 (5.132-23.237) 6.471 (3.506 8.060) 17.045 (10.58(/-21.002) 24.786 (15.252-29.868)
0.033
0.8
0.021 0.(/09 09 0.4 0.96
288
A. A. TOOGOOD AND S. M. SHALET
The fat-free mass determined by DEXA comprises cell mass and extracellular fluid; the former can be determined from estimates of total body potassium, the latter by various dilution techniques. Several studies have shown that there is a reduction in fat-free tissue in younger GH-deficient adults; however, Rosen et al (1993b) found that in GH-deficient adults over the age of 50 the reduction in body cell mass was no longer apparent. Thus it appears that the effects of GH deficiency on body composition are attenuated in the elderly, the major impact being on fat mass. Bone mineralization and bone turnover
The accrual of bone mineral takes place during adolescence and continues at a somewhat diminished rate during early adult life (Bonjour et al, 1991; Theintz et al, 1992). There is evidence to suggest that peak bone mass is reached during the third or even the early part of the fourth decade of life (Hall et al, 1990). Once peak bone mass has been attained there is a gradual decline in bone mineral with increasing age (Smith, 1967; Raisz, 1988). Adults who are GH-deficient have been shown to have a significant reduction in bone mineral density (BMD) compared with healthy agematched controls (Hyer et al, 1992; Rosen et al, 1993a; Holmes et al, 1994); indeed, this is currently considered to be one of the major indications for the provision of GH replacement therapy in adult life (Shalet, 1996). The severity of osteopenia appears to be related to the age of onset of GH deficiency. Patients with childhood-onset GH deficiency have more marked osteopenia (O'Halloran et al, 1993) compared with those who become GH deficient in adult life (Holmes et al, 1994). In our group of GH-deficient subjects over the age of 60 years, bone mineral density, determined by DEXA, was not significantly reduced at the hip or the lumbar spine compared with the controls (Table 2) (Toogood et al, 1997b). Similar findings have recently been reported by a group from Japan who studied slightly younger patients (mean age 52 years) (Kaji et al, 1997). Despite failing to demonstrate osteopenia in the elderly with GH deficiency, serum osteocalcin and urinary deoxypyridinoline X-links, Table 2. Bone mineral density, expressed as age-specific z-scores, and markers of bone formation and resorption in elderly patients with GH deficiency and healthy controls.
L2-L4 Femoral neck Femoral trochanter Ward's triangle Serum osteocalcin (p.g/1) Deoxypyridinoline X-link:creatinine (p.mol/mol)
Patients
Controls
P
0.80 (-2.83-2.95) 0.27 (-1.48-3.43) 0.46 (-2.14-3.37) 0.1 (-1.58-3.94) 11.5 (3.6-23.0) 3.5 (0.8-8.3)
1.10 (-2.87-2.64) 0.25 (-2.29-3.26) 0.5 (-2.4-3.8) 0.47 (-2.45-3.31) 15.1 (0.7-40.5) 4.9 (3.0-9.7)
0.68 0.89 0.98 0.96 0.019 0.038
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289
markers of bone formation and resorption, were reduced, suggesting a reduction in bone turnover (Table 2). In healthy elderly adults it has been shown that a reduction in bone turnover may actually protect against fractures (Garnero et al, 1996). Thus, rather than being at an increased risk of fracture as demonstrated in younger GH deficient adults, the elderly with organic GH deficiency may be protected from osteoporotic fractures. Further studies are required to determine whether the reduction in bone turnover observed in the elderly with GH deficiency, who have normal BMD, is of clinical significance, and whether GH replacement therapy in this age group modifies the risk of fracture.
DISTINGUISHING ORGANIC GH DEFICIENCY FROM AGE-RELATED HYPOSOMATOTROPISM The studies outlined above have demonstrated that the elderly with hypothalamic-pituitary disease have GH deficiency distinct from the agerelated decline in GH secretion. The reduction in GH secretion is sufficient to cause significant changes in serum IGF-1 concentrations, body composition and bone metabolism. The implication of these data is that the elderly with organic GH deficiency may benefit from GH replacement therapy. Studies in younger adults with hypothalamic-pituitary disease have shown that those who perceive the greatest benefit from GH replacement are those with more severe GH deficiency (Holmes et al, 1995). In the elderly, in whom the effects of GH deficiency appear to be attenuated, it is likely that only those with very severe GH deficiency will perceive any degree of benefit from GH replacement therapy. Such patients need to be identified effectively and safely. We have already seen that the degree of overlap observed in serum concentrations of IGF-1 and IGFBP-3 between patients and controls is considerable and excludes both as markers of GH deficiency in the elderly. Even assessment of spontaneous GH secretion failed to separate patients from controls; furthermore, the 24-hour profile is not a pragmatic method of defining GH status for routine clinical practice. Currently the most effective method of distinguishing GH deficiency from normality is a dynamic test of GH status (Shalet et al, 1998). The test most frequently quoted in the literature as the 'gold standard' is the insulin tolerance test (ITT) (Hoffman et al, 1994; Toogood et al, 1994), although other tests are being developed which may supercede the ITT (Ghigo et al, 1996). The ITT is potentially hazardous in the elderly who may have clinical or subclinical ischaemic heart disease. The arginine stimulation test (AST) is an alternative provocation test, although arginine is not as potent a secretagogue as the ITT (Rahim et al, 1996). The GH response to arginine is not influenced by age; side-effects of arginine infusion are limited to mild dizziness, and it appears to be much safer in the elderly, including those with overt ischaemic heart disease. For these reasons we chose the AST to study stimulated GH secretion in the elderly (Toogood et al, 1998).
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There was an excellent correlation between spontaneous GH secretion and the stimulated GH peak in both patients with hypothalamic-pituitary disease (r=0.89, P<0.0001) and healthy controls (r=0.56, P=0.005). Figure 1 demonstrates, however, that the AST was not able completely to separate patients from controls. The lowest GH peak in the controls was 1.8 g/l. If a peak GH value of less than 1.5 [tg/l is used as the diagnostic threshold for GH deficiency then the sensitivity of the AST is 77% with a specificity of 100%. If the three patients with isolated GH deficiency are excluded, the sensitivity of the AST rises to 86%. We have, therefore, suggested that a GH peak of 1.5 ~tg/1 be used to indicate impaired GH secretion in patients over the age of 60 years, We have previously demonstrated that the severity of GH deficiency increases as the number of anterior pituitary hormone deficits increases. Some 90% of patients with two or three hormone deficiencies, in addition to GH, had a GH peak to an ITT less than 2 ~tg/1 (Toogood et al, 1994). In the elderly, using similar methods, 89% of the patients with two or three additional anterior pituitary hormone deficits had a GH peak response to arginine less than 0.8 j.tg/1 (1 gg/1 = 2.6 mU/1), a level consistent with severe GH deficiency (Toogood et al, 1998).
GH replacement therapy in the elderly with organic hypothalamic-pituitary disease The majority of the studies of GH replacement therapy in adults have been limited to patients under the age of 60 years, GH deficiency in this age group does cause significant abnormalities that appear to be reduced in severity compared with the effects observed in younger adults. Despite this attenuation, it is possible that the elderly with organic GH deficiency will gain benefit from GH replacement therapy. The dose of GH replacement in GH deficient adults who are over 60 years old is lower than that used in younger patients. We recently completed a dose-finding study in the elderly with organic GH deficiency which examined the effects of three doses, 0.17, 0.33 and 0.5mg per day (1 r a g - 3 IU) of GH therapy on serum markers. One of the stated aims of GH therapy is to maintain the serum IGF-1 within the normal range (Growth Hormone Research Society, 1998). In our study, 0,5 mg of GH per day, administered subcutaneously at night, elevated the serum IGF-1 concentration above the age-specific normal range in 50% of subjects. At this dose three patients developed side-effects, requiring a dose reduction in two of them. A dose of 0.33 mg/day resulted in an IGF-1 concentration in the upper part of the normal range in all subjects and was not associated with side-effects. This replacement dose is considerably less than that used in younger adult patients with GH deficiency. During the study we assessed the effects of GH replacement therapy on body composition using DEXA, and quality of life using a diseasespecific questionnaire (Holmes et al, 1995). There was a significant fall in fat mass and also an increase in lean body mass. The quality of life data were difficult to interpret as they were confounded by the age of the
A G E I N G A N D G R O W T H H O R M O N E STATUS
291
patients and the design of the study. Using a disease-specific validated questionnaire we were, however, able to demonstrate a significant improvement in quality of life after 6 months of GH replacement therapy (Toogood et al, 1997a). This study provides evidence that the elderly with organic GH deficiency derive benefit from GH replacement in the short term. Further studies are required to determine whether these changes persist.
GH therapy in healthy elderly subjects Ageing is associated with a fall in GH secretion and physiological changes similar to those observed in younger adults who have organic GH deficiency. The beneficial effects of GH replacement reported in patients with organic GH deficiency led to the suggestion that GH treatment in the elderly would improve body composition, BMD and muscle strength. One early study used GH to increase the serum IGF-1 of healthy men into the range observed in adults in their twenties (Rudman et al, 1990). Over a 6-month period, GH therapy resulted in an increase in lean mass, a decrease in fat mass and a significant rise in vertebral BMD. Despite the significant gains in muscle mass observed with GH therapy, actual muscle strength did not improve (Taafe et al, 1994). The increase in BMD observed in adults who received GH replacement therapy for organic GH deficiency suggested that it may be useful in the management of primary osteoporosis. Unfortunately the gains in BMD are similar to those seen with less expensive anti-resorptive compounds, such as the bisphosphonates, which can be taken orally (Marcus et al, 1993). Side-effects of GH therapy were common in elderly subjects who received it in studies aiming to reverse the hyposomatotropism of age. Subjects frequently required dose reduction, or were withdrawn from the study, when they developed oedema, carpal tunnel syndrome and occasionally gynaecomastia (Cohn et al, 1993; Holloway et al, 1994; Taafe et al, 1994). The high incidence of side-effects in elderly subjects who do not have organic GH deficiency limits the use of GH therapy considerably. At the present time, there are no data on the long-term effects, beneficial or otherwise, of GH therapy given to healthy elderly subjects. In a recent study the potential dangers that may be associated with artificially increasing the serum IGF-1 concentration were illustrated. Chan et al (1998) found a strong correlation between serum IGF-1 concentrations and the risk of developing prostate cancer. Subjects taking part in the Physicians' Health Study who developed prostate cancer had significantly higher serum IGF-1 concentrations at enrollment into the study compared with age-matched controls. The relationship between the relative risk of developing prostate cancer and serum IGF-1 concentration was particularly pronounced in men over 60 years of age. This study serves to emphasize that great caution is required before long-term GH therapy is offered to the normal elderly.
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CONCLUSIONS The decline in growth hormone secretion associated with increasing age runs in parallel with the changes in body composition, reduction in muscle strength and BMD which occur as we grow older. Hypothalamic-pituitary disease in the elderly results in a highly significant reduction in GH secretion compared with healthy age-matched controls. Although this degree of GH deficiency is sufficient to cause a reduction in serum IGF-1 and abnormalities of body composition, the severity of the changes are greatly attenuated compared to the changes observed in younger adults who have GH deficiency. A study of GH replacement therapy in patients over the age of 60 years who have organic GH deficiency resulted in a rise in serum IGF-1 concentration and changes in body composition, and suggested that these patients do receive some benefit in terms of improved quality of life. GH therapy used in adults who did not have organic disease of the hypothalamicpituitary axis resulted in a high incidence of side-effects, and, although lean body mass increased and fat mass fell, did not cause a significant improvement in muscle strength. The biological changes associated with 90% reduction in GH secretion caused by organic disease of the hypothalamic-pituitary axis in the elderly are greatly attenuated compared with the effects observed in younger adults. This suggests that the decline in GH with increasing age does not play a major role in the ageing changes that affect body composition and the skeleton. This, together with the recent findings that serum IGF-1 concentrations in the upper rather than lower part of the normal range increase the risk of prostate cancer, suggests that GH therapy is not appropriate in the elderly who do not have organic GH deficiency. We should also be cautious in the use of GH in those elderly patients with organic disease of the hypothalamic-pituitary axis, and ensure careful monitoring to keep the IGF-1 level within the normal range.
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